Study On The Biological Function Of Zebrafish TAMM41 In Cardiac Development And PDCD11 In Hematopoietic Development

TAMM41,a mitochondrial membrane maintenance protein,was previously reported to be critical for yeast survival,but its function in higher vertebrates remains unknown.Here,through screening of the congenital heart diseases(CHD)sensitive region of 3p25 deletion syndrome among 118 sporadic atrioventricular septal defect(AVSD)patients,we identified three AVSD cases carrying heterozygous intronic mutations of TAMM41.All three cases lacked normal full-length Tamm41 transcripts,most likely due to specific expression of the mutant allele.Furthermore,our in vivo zebrafish model studies clearly demonstrated that Tamm41 is critical for normal cardiogenesis in higher vertebrates.Molecular mechanistic studies revealed that TAMM41 interacts and modulates the PINK1-PARK2 dependent mitophagy pathway,thereby implicating TAMM41 in heart valve development and cardiomyocyte proliferation during zebrafish embryonic cardiogenesis.Our studies highlight essential roles for TAMM41-dependent mitophagy in development of the heart and provide novel insights into the aetiology of AVSD.Tissue resident macrophages have pivotal roles in tissue homeostasis and organ inflammation.In recent years,the new paradigm has suggested the distinct origin and regulatory mechanisms of tissue resident macrophages,which comes from embryonic hematopoiesis,with monocytes from the bone marrow(BM).In this study,we identified a novel protein,programmed cell death protein,PDCD11,whose deficiency specifically influenced the development of tissue resident macropahges in zebrafish.Further study into the mechanisms we found that through differential regulation of P65 and c-Rel,two transcription factors of NF kappa B family,PDCD11 fulfilled the preciseregulation of the fate of primitive myeloid cells.